{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T06:02:42Z","timestamp":1783749762339,"version":"3.55.0"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T00:00:00Z","timestamp":1559779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundaci\u00f3n S\u00e9neca (Regi\u00f3n de Murcia, Spain)","award":["20810\/PI\/18"],"award-info":[{"award-number":["20810\/PI\/18"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>New three-dimensionally-structured hybrid phospholipid vesicles, able to load clotrimazole in a high amount (10 mg\/mL), were obtained for the first time in this work by significantly reducing the amount of water (\u226410%), which was replaced with a mixture of glycerol and ethanol (\u224890%). A pre-formulation study was carried out to evaluate the effect of both the composition of the hydrating medium and the concentration of the phospholipid on the physico-chemical properties of hybrid vesicles. Four different three-dimensionally-structured hybrid vesicles were selected as ideal systems for the topical application of clotrimazole. An extensive physico-chemical characterization performed using transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM), 31P-NMR, and small-angle X-ray scattering (SAXS) displayed the formation of small, multi-, and unilamellar vesicles very close to each other, and was capable of forming a three-dimensional network, which stabilized the dispersion. Additionally, the dilution of the dispersion with water reduced the interactions between vesicles, leading to the formation of single unilamellar vesicles. The evaluation of the in vitro percutaneous delivery of clotrimazole showed an improved drug deposition in the skin strata provided by the three-dimensionally-structured vesicles with respect to the commercial cream (Canesten\u00ae) used as a reference. Hybrid vesicles were highly biocompatible and showed a significant antifungal activity in vitro, greater than the commercial cream Canesten\u00ae. The antimycotic efficacy of formulations was confirmed by the reduced proliferation of the yeast cells at the site of infection in vivo. In light of these results, clotrimazole-loaded, three-dimensionally-structured hybrid vesicles appear to be one of the most innovative and promising formulations for the treatment of candidiasis infections.<\/jats:p>","DOI":"10.3390\/pharmaceutics11060263","type":"journal-article","created":{"date-parts":[[2019,6,7]],"date-time":"2019-06-07T03:56:31Z","timestamp":1559879791000},"page":"263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Optimization of Innovative Three-Dimensionally-Structured Hybrid Vesicles to Improve the Cutaneous Delivery of Clotrimazole for the Treatment of Topical Candidiasis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3787-257X","authenticated-orcid":false,"given":"Maria Letizia","family":"Manca","sequence":"first","affiliation":[{"name":"Department Scienze della Vita e dell\u2019Ambiente, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Usach","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Burjassot, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Esteban","family":"Peris","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Burjassot, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Ibba","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Cagliari, Molecular Biology Service Lab (MBS), Via Ospedale 40, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germano","family":"Orr\u00f9","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Cagliari, Molecular Biology Service Lab (MBS), Via Ospedale 40, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department Scienze della Vita e dell\u2019Ambiente, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Escribano-Ferrer","sequence":"additional","affiliation":[{"name":"Biopharmaceutics and Pharmacokinetics Unit, Institute for Nanoscience and Nanotechnology, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5331-9029","authenticated-orcid":false,"given":"Juan Carmelo","family":"Gomez-Fernandez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology A, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, 30080 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"Aranda","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology A, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, 30080 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Fadda","sequence":"additional","affiliation":[{"name":"Department Scienze della Vita e dell\u2019Ambiente, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-2344","authenticated-orcid":false,"given":"Maria","family":"Manconi","sequence":"additional","affiliation":[{"name":"Department Scienze della Vita e dell\u2019Ambiente, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,6]]},"reference":[{"key":"ref_1","unstructured":"Jim, E.R., and Nancy, A.M.R. (2014). Candida Albicans Infections. Reference Module in Biomedical Sciences, Elsevier."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/1523-1747.ep12478053","article-title":"Experimental Cutaneous Candidiasis In Rodents","volume":"66","author":"Ray","year":"1976","journal-title":"J. Investig. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5385","DOI":"10.1128\/JB.183.18.5385-5394.2001","article-title":"Biofilm formation by the fungal pathogen Candida albicans: Development, architecture, and drug resistance","volume":"183","author":"Chandra","year":"2001","journal-title":"J. Bacteriol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1128\/CMR.12.4.501","article-title":"Antifungal agents: Mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance","volume":"12","author":"Ghannoum","year":"1999","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/j.1365-2133.1973.tb02978.x","article-title":"Comparison of clotrimazole cream, Whitfield\u2019s ointment and Nystatin ointment for the topical treatment of ringworm infections, pityriasis versicolor, erythrasma and candidiasis","volume":"89","author":"Clayton","year":"1973","journal-title":"Br. J. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"424","DOI":"10.2165\/00003495-197509060-00003","article-title":"Clotrimazole","volume":"9","author":"Sawyer","year":"1975","journal-title":"Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/jps.20666","article-title":"Deep Percutaneous Penetration into Muscles and Joints","volume":"95","author":"Lee","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_8","first-page":"56","article-title":"New Formulation Strategies in Topical Antifungal Therapy","volume":"3","author":"Aksu","year":"2013","journal-title":"J. Cosmet. Dermatol. Sci. Appl."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2006.12.005","article-title":"Lipid vesicles for skin delivery of drugs: Reviewing three decades of research","volume":"332","author":"Elsayed","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0928-0987(01)00167-1","article-title":"Novel Mechanisms and Devices to Enable Successful Trans Dermal Drug Delivery","volume":"14","author":"Barry","year":"2001","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ddtec.2005.05.003","article-title":"Vesicles as a tool for transdermal and dermal delivery","volume":"2","author":"Bouwstra","year":"2005","journal-title":"Drug Discov. Today Technol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/j.2042-7158.1982.tb04767.x","article-title":"Liposomes--a selective drug delivery system for the topical route of administration: Gel dosage form","volume":"34","author":"Mezei","year":"1982","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0005-2736(01)00369-8","article-title":"New, highly efficient formulation of diclofenac for the topical, transdermal administration in ultradeformable drug carriers, Transfersomes","volume":"1514","author":"Cevc","year":"2001","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0005-2736(97)00177-6","article-title":"Ultraflexible vesicles, Transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin","volume":"1368","author":"Cevc","year":"1998","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ijpharm.2016.06.136","article-title":"Inhibition of skin inflammation by baicalin ultradeformable vesicles","volume":"511","author":"Caddeo","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0168-3659(99)00222-9","article-title":"Ethosomes\u2014novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties","volume":"65","author":"Touitou","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1016\/S0142-9612(00)00063-6","article-title":"Carriers for skin delivery of trihexyphenidyl HCl: Ethosomes vs. liposomes","volume":"21","author":"Dayan","year":"2000","journal-title":"Biomaterials"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1080\/10717540500176910","article-title":"Testosterone Ethosomes for Enhanced Transdermal Delivery","volume":"12","author":"Ainbinder","year":"2005","journal-title":"Drug Deliv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jconrel.2005.04.007","article-title":"Ethosomes for skin delivery of ammonium glycyrrhizinate: In vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers","volume":"106","author":"Paolino","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.colsurfa.2009.04.006","article-title":"Development and characterization of liposomes containing glycols as carriers for diclofenac","volume":"342","author":"Manconi","year":"2009","journal-title":"Colloids Surf. A Physicochem. Eng. Asp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ijpharm.2013.07.060","article-title":"Glycerosomes: A new tool for effective dermal and transdermal drug delivery","volume":"455","author":"Manca","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.colsurfb.2014.09.059","article-title":"Improvement of quercetin protective effect against oxidative stress skin damages by incorporation in nanovesicles","volume":"123","author":"Manca","year":"2014","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.colsurfb.2016.03.044","article-title":"Inhalable polymer-glycerosomes as safe and effective carriers for rifampicin delivery to the lungs","volume":"143","author":"Melis","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Manca, M.L., Cencetti, C., Matricardi, P., Castangia, I., Zaru, M., Sales, O.D., Nacher, A., Valenti, D., Maccioni, A.M., and Fadda, A.M. (2016). Glycerosomes: Use of hydrogenated soy phosphatidylcholine mixture and its effect on vesicle features and diclofenac skin penetration. Int. J. Pharm., 511.","DOI":"10.1016\/j.ijpharm.2016.07.009"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.biomaterials.2015.08.034","article-title":"Development of curcumin loaded sodium hyaluronate immobilized vesicles (hyalurosomes) and their potential on skin inflammation and wound restoring","volume":"71","author":"Manca","year":"2015","journal-title":"Biomaterials"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.carbpol.2015.08.037","article-title":"Delivery of liquorice extract by liposomes and hyalurosomes to protect the skin against oxidative stress injuries","volume":"134","author":"Castangia","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"ref_27","unstructured":"Manca, M.L., Manconi, M., Zaru, M., Castangia, I., Cabras, A., Cappai, N., and Fadda, A.M. (2014). Ialurosomi, Loro Uso in Composizioni Topiche Farmaceutiche o Cosmetiche e Relativo Procedimento di Preparazione. (ITRM20,140,687, 102,014,902,312,901), U.S. Patent."},{"key":"ref_28","unstructured":"Manca, M.L., Manconi, M., and Fadda, A.M. (2018). Phospholipid Threedimensional Vesicular Aggregates Scattered in Alcoholic Mixtures with No or Low Water Content, Their Preparation and Use in Formulations for Topical Application. (n.EP18163201.9), EU Patent Application."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/jps.22775","article-title":"Liposomes coated with chitosan-xanthan gum (chitosomes) as potential carriers for pulmonary delivery of rifampicin","volume":"101","author":"Manca","year":"2011","journal-title":"J. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4000","DOI":"10.1103\/PhysRevE.62.4000","article-title":"Structural information from multilamellar liposomes at full hydration: Full q-range fitting with high quality x-ray data","volume":"62","author":"Pabst","year":"2000","journal-title":"Phys. Rev. E"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1107\/S0021889803017527","article-title":"Structural analysis of weakly ordered membrane stacks","volume":"36","author":"Pabst","year":"2003","journal-title":"J. Appl. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.ijpharm.2014.10.031","article-title":"Development of novel diolein-niosomes for cutaneous delivery of tretinoin: Influence of formulation and in vitro assessment","volume":"477","author":"Manca","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105149","DOI":"10.1039\/C5RA24032H","article-title":"Nanoincorporation of curcumin in polymer-glycerosomes and evaluation of their in vitro-in vivo suitability as pulmonary delivery systems","volume":"5","author":"Manca","year":"2015","journal-title":"RSC Adv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.colsurfb.2016.07.043","article-title":"Polymer-associated liposomes for the oral delivery of grape pomace extract","volume":"146","author":"Manconi","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_35","first-page":"82","article-title":"Azole Resistance and ERG11 464 Polymorphism in Oral Candida albicans Clinical Strains Isolated in Sardinia","volume":"2","author":"Ciusa","year":"2019","journal-title":"Open Mycol. J."},{"key":"ref_36","first-page":"35","article-title":"Comparison of Clinical Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution methods for determining the susceptibilities of Candida isolates","volume":"52","author":"Dalyan","year":"2018","journal-title":"Mikrobiyol. Bul."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.jinorgbio.2017.02.015","article-title":"[Au(pyb-H)(mnt)]: A novel gold(III) 1,2-dithiolene cyclometalated complex with antimicrobial activity (pyb-H = C-deprotonated 2-benzylpyridine; mnt = 1,2-dicyanoethene-1,2-dithiolate)","volume":"170","author":"Pintus","year":"2017","journal-title":"J. Inorg. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ejpb.2017.02.004","article-title":"Bifunctional viscous nanovesicles co-loaded with resveratrol and gallic acid for skin protection against microbial and oxidative injuries","volume":"114","author":"Vitonyte","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.3389\/fmicb.2017.02067","article-title":"The Selective Interaction of Pistacia lentiscus Oil vs. Human Streptococci, an Old Functional Food Revisited with New Tools","volume":"8","author":"Demontis","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"164267","DOI":"10.1155\/2013\/164267","article-title":"Oil Essential Mouthwashes Antibacterial Activity against Aggregatibacter actinomycetemcomitans: A Comparison between Antibiofilm and Antiplanktonic Effects","volume":"2013","author":"Erriu","year":"2013","journal-title":"Int. J. Dent."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.chemphyslip.2012.01.006","article-title":"Development, characterization and in vivo assessment of effective lipidic nanoparticles for dermal delivery of fluconazole against cutaneous candidiasis","volume":"Volume 165","author":"Richard","year":"2012","journal-title":"Chemistry and Physics of Lipids"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0732-8893(00)00165-6","article-title":"Sustained gastrointestinal colonization and systemic dissemination by Candida albicans, Candida tropicalis and Candida parapsilosis in adult mice","volume":"38","author":"Mellado","year":"2000","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.colsurfb.2013.07.014","article-title":"Close-packed vesicles for diclofenac skin delivery and fibroblast targeting","volume":"111","author":"Manca","year":"2013","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"32","DOI":"10.18433\/J3PP4K","article-title":"Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures","volume":"11","author":"Jouyban","year":"2008","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s002490000077","article-title":"Formation of unilamellar vesicles by repetitive freeze-thaw cycles: Characterization by electron microscopy and 31P-nuclear magnetic resonance","volume":"29","author":"Warschawski","year":"2000","journal-title":"Eur. Biophys. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.ijpharm.2016.04.008","article-title":"Combination of argan oil and phospholipids for the development of an effective liposome-like formulation able to improve skin hydration and allantoin dermal delivery","volume":"505","author":"Manca","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_47","unstructured":"Ali, D.S. (2014). Liposomes as Potential Drug Carrier Systems for Drug Delivery. Application of Nanotechnology in Drug Delivery, Scitus Academics Llc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1166\/jnn.2014.9080","article-title":"Liposomes: Versatile and Biocompatible Nanovesicles for Efficient Biomolecules Delivery","volume":"14","author":"Mallick","year":"2014","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.colsurfb.2014.03.010","article-title":"Molecular arrangements and interconnected bilayer formation induced by alcohol or polyalcohol in phospholipid vesicles","volume":"117","author":"Manca","year":"2014","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ijpharm.2018.11.002","article-title":"Biopharmaceutical profile of a clotrimazole nanoemulsion: Evaluation on skin and mucosae as anticandidal agent","volume":"554","author":"Souto","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1208\/s12249-011-9653-7","article-title":"Formulation, Characterization, and Clinical Evaluation of Microemulsion Containing Clotrimazole for Topical Delivery","volume":"12","author":"Hashem","year":"2011","journal-title":"AAPS Pharm. Sci. Tech."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1208\/s12249-012-9754-y","article-title":"Cavamax W7 composite ethosomal gel of clotrimazole for improved topical delivery: Development and comparison with ethosomal gel","volume":"13","author":"Akhtar","year":"2012","journal-title":"AAPS Pharm. Sci. Tech."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"780","DOI":"10.5301\/ijao.5000170","article-title":"Antifungal Activity against Candida Biofilms","volume":"35","year":"2012","journal-title":"Int. J. Artif. 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